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Bisphosphonates and current treatments of bone pain

Majority of treatments applied for pain treatment in malignant and non-malignant bone disorders are similar to other pain disorders and their main differences are determined primarily by the severity of the disease. Common (non-specific) chronic pain treatment includes non-steroid anti-inflammatory drugs (NSAIDS) (Fu et al., 2015) and different opioids (Yaldo et al., 2016). Their efficacy is still limited by various adverse side effects and

NSAIDS often provide insufficient pain relief. Thus, in many cases, bone pain cannot be resolved by common current therapies what strongly decrease quality of life (van den Beuken-van Everdingen et al., 2007, 2016; Coleman et al., 2014). In fact, currently, pain management of malignant bone disorders is considered as not satisfactory (Smith and Mohsin, 2013). Currently 85-95% of patients with bone cancer have significant malignancy-induced pain and 45% of these patients collide with an inadequate pain control therapy or unmanaged pain (Smith and Mohsin, 2013). Also, many NSAIDs treatments are not sufficient to decrease skeletal pain or have not strong enough effect in consideration of the personal side effect risks (Rasmussen-Barr et al., 2017). In addition, it is well known that NSAIDs have side effects including the gastrointestinal and cardiovascular complications (Sostres et al., 2010). In particular, they injure the upper and lower gut by depleting COX-1 derived prostaglandins causing the peptic ulcer (Sostres et al., 2010). Also, recent clinical meta-analysis found a direct link of NSAIDs treatment to the heart failure (Arfè et al., 2016).

Another major issue to consider is that some typical NSAIDs such as ibuprofen and Cox-2 inhibitors slow down fracture healing in animal models of bone fracture (O’Connor et al., 2009; Barry, 2010).

Therefore, new approaches to the chronic bone pain control are strongly needed. Ideally, if the analgesic effect is associated with promotion of the bone formation and with skeletal healing or, at least, the anti-nociception develops in the absence of bone healing inhibition.

2.4.2 Beneficial effects of the BPs for bone pain treatment

Currently, bisphosphonates (BPs) are the safest treatments for bone disorders associated with bone lesions. BPs are highly specific to the hard bone tissue containing hydroxyapatite. BPs are divided into two types: i) compounds lacking a nitrogen group (non-NBP) (Frith et al., 2001; Räikkönen et al., 2009; Rogers et al., 2011) and ii) nitrogen-containing compounds (NBP).

Interestingly, both type of BPs can induce the formation of endogenous ATP-analogues as represented on Fig 5. Thus, non-NBPs promote the synthesis of compounds with ApCp-groups, whereas NBPs induce IPP/DMAPP (Isopentenyl pyrophosphate/dimethylallyl pyrophosphate) and the ApppI (1-adenosin-5’-yl ester 3-(3-methylbut-3-enyl) ester). Since these are relatively recently discovered compounds, their roles in health and disease are still far from clear.

Figure 5. Scheme of the cellular mechanism of BPs (top). Induction of the ATP analogues by BPs (bottom). Adopted from Russell, 2011.

Both non-NBPs and NBPs have anti-osteoclast and anti-cancer activity (Fig 5 and 6). They can interfere with mitochondrial ATP production or inhibit the mevalonate pathway and activate caspases (Fromigue et al., 2000; Oades et al., 2003; Green, 2004; Koshimune et al., 2007; Tanaka et al., 2013). Recently, evidence emerging from clinical studies has suggested that BPs, in combination with other treatment modalities, can diminish pain in cancer patients (Body et al., 2004; Tagiyev et al., 2016). Other clinical research findings have indicated that BPs can successfully reduce the level of persistent pain not only in bone disorders, but also in patients with chronic low back pain and complex regional pain syndrome type I (Haslbauer and Fiegl, 2009; Abe et al., 2011; Pappagallo et al., 2014).

In general, the anti-nociceptive effect of BPs can be either direct or indirect, mediated by production of endogenous ATP-analogues. For instance, there is a strong correlation between BPs’ anti-resorptive and anti-tumor effects and their ability to induce the formation of endogenous ATP-analogues (ApppI, IPP, AppCClp) in vivo (Ramanlal Chaudhari et al., 2012). Additionally, it has been proposed that BP-induced formation of ATP derivatives can participate in pain relief (Fromigue et al., 2000; Hadji et al., 2016). In particular, NBPs represent the most effective group, pointing to a possible involvement of ApppI and IPP in analgesia.

Notably, BPs induced analgesia could involve even more complicated pathways including modification of the immune response. Thus, two NBPs, zoledronate and residronate, activated human Vγ9Vδ2 T-cells, which have potent anti-tumor properties (Benzaïd et al.,

2011, 2012). NBP pre-treated monocytes accumulate ApppI and IPP, contributing to the activation and proliferation of Vγ9Vδ2 T-cells (Roelofs et al., 2009). After NBP treatment, high levels of ApppI/IPP accumulate in cancer cells and these can be released during the apoptosis of tumor cells to activate surrounding bone cells and sensory nerve terminals. These findings suggest a novel, but largely unexplored, immune anti-tumor and anti-nociceptive effect for BPs.

Administration of BPs in patients with different bone cancers and metastases is intended not only to reduce tumor size and prevent bone fracture but also to provide pain relief (Yuen et al., 2006; Haslbauer and Fiegl, 2009; Lopez-Olivo et al., 2012). According to the Cochrane Reviews, there is evidence supporting the pain relief effectiveness of BPs in bone malignancy, although the analgesic effect of BPs is not so strong as obtained with morphine (Wong and Wiffen, 2002). However, when the other methods of pain relief are inadequate or strong opioids should be avoided, then treatment with BPs can be beneficial in patients with bone tumors (Wong and Wiffen, 2002). On the other hand, the clinical use of BPs for pain diseases in non-malignant bone disorders has achieved good results even without additional therapies. There was an improvement in the regional osteoporotic changes and reduced pain after administration of a low-dose of BPs in individuals with a complex regional pain syndrome type I (Abe et al., 2011). Likewise, in patients with chronic low back pain, these workers found evidence for the analgesic efficacy of the BP, pamidronate (Pappagallo et al., 2014).

In general, the analgesic efficiency of BPs in clinical research significantly increased the interest of scientists in investigating the molecular mechanisms behind the anti-nociceptive in conjunction with the pro-apoptotic effects of BPs on tumor cells. The latter could be due to the ability of BPs to inhibit the release of bone-stored growth factors, thus reducing the growth of the bone tumor. Interestingly, the pro-apoptotic action of BPs on tumor cells has been associated with the anti-apoptotic effects of these medicines on osteoblasts and osteocytes, a property that positively influences bone homeostasis (Bellido and Plotkin, 2011).

This important mechanism for bone survival is illustrated in Fig 6.

The decrease in the size of the lesions induced by BPs diminishes the acidic bone microenvironment, leading to less activation of the acid sensitive pro-nociceptive ASIC and TRP channels (Nagae et al., 2007). Thus, two non-NBPs, clodronate and etidronate, have been shown to reduce capsaicin-induced hyperalgesia in an inflammatory pain model and to decrease the number of c-Fos positive neurons in spinal cord (Kim et al., 2013). Similar results have been published for two NBPs, zoledronate and alendronate. Thus, zoledronate has decreased the mRNA expression of ASIC1a and ASIC1b as well as that of c-Fos in different pain models: (i) inflammatory pain (induced by injections in the hind-paw of the f PTH-rP or CFA) (Nagae et al., 2006) and (ii) a bone cancer model (Nagae et al., 2007). A recent study has demonstrated that alendronate effectively reduced the development of hyperalgesia in a rat model of ovariectomy-induced bone loss (Naito et al., 2017). Interestingly, a very unique direct effect on the pro-nociceptive ATP-gated receptors has been described forthe NBP, minodronic acid, which belongs to the third generation of these medicines. This NBP exerted a direct inhibitory effect on the pro-nociceptive P2X3 and P2X2/3 receptors and it showed evidence of analgesia in animal pain models (Kakimoto et al., 2008; Tanaka et al., 2017).

Figure 6. Schematic representation of BPs-induced molecular mechanisms involved in analgesia, present in the environment of a bone malignancy.

Figure shows receptors (P2X3, ASICs, TRPV3, TRPA1) and pro-nociceptive endogenous compounds (H+, IPP, ApppI, ATP, BPs) implicated in bone pain (explained in the main abbreviation list).

Thus, accumulated evidence suggests that the very specific

involvement of the BPs themselves and the BPs-induced ATP derivatives are both involved in anti-nociception. Both types of BPs can evoke analgesic effects, but the exact mechanisms are not fully understood. These effects can vary depending on the BPs type and will need to be examined in further studies.